{ "id": "epc0ndarj2", "slug": "cyclophosphamide-dexamethasone-regimen", "title": "Cyclophosphamide/dexamethasone regimen", "updated": "2026-10-15", "topic_path": [ { "id": "life", "label": "Life and health", "api_url": "https://www.edgepedia.org/api/v1/topics/life" }, { "id": "life.health", "label": "Human health and medicine", "api_url": "https://www.edgepedia.org/api/v1/topics/life.health" }, { "id": "life.health.medicines", "label": "Medicines and therapeutics", "api_url": "https://www.edgepedia.org/api/v1/topics/life.health.medicines" }, { "id": "life.health.medicines.cancer-chemotherapy", "label": "Cancer chemotherapy and regimens", "api_url": "https://www.edgepedia.org/api/v1/topics/life.health.medicines.cancer-chemotherapy" }, { "id": "life.health.medicines.cancer-chemotherapy.multiple-myeloma-and-hematologic-regimens", "label": "Multiple myeloma and hematologic regimens", "api_url": "https://www.edgepedia.org/api/v1/topics/life.health.medicines.cancer-chemotherapy.multiple-myeloma-and-hematologic-regimens" } ], "geo": [ { "id": "geo.nongeo.t1946.life.health.medicines.cancer-chemotherapy", "label": "Non-geographic · 1946 to 2000: Cancer chemotherapy and regimens", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.t1946.life.health.medicines.cancer-chemotherapy", "path": [ { "id": "geo.nongeo", "label": "Non-geographic", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo" }, { "id": "geo.nongeo.t1946", "label": "Non-geographic · 1946 to 2000", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.t1946" }, { "id": "geo.nongeo.t1946.life", "label": "Life and health", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.t1946.life" }, { "id": "geo.nongeo.t1946.life.health", "label": "Human health and medicine", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.t1946.life.health" }, { "id": "geo.nongeo.t1946.life.health.medicines", "label": "Medicines and therapeutics", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.t1946.life.health.medicines" }, { "id": "geo.nongeo.t1946.life.health.medicines.cancer-chemotherapy", "label": "Cancer chemotherapy and regimens", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.t1946.life.health.medicines.cancer-chemotherapy" } ] } ], "excerpt": "The cyclophosphamide/dexamethasone (Cy-Dex) regimen is a chemotherapy combination pairing the alkylating agent cyclophosphamide with the corticosteroid dexamethasone, formerly used as induction therapy for multiple myeloma before stem cell transplantation.", "snippet": "The cyclophosphamide/dexamethasone (Cy-Dex) regimen is a chemotherapy combination pairing the alkylating agent cyclophosphamide with the corticosteroid dexamethasone, formerly used as induction therapy for multiple myeloma before stem cell transplantation.", "node": "life.health.medicines.cancer-chemotherapy.multiple-myeloma-and-hematologic-regimens", "markdown": "# Cyclophosphamide/dexamethasone regimen\n\nThe cyclophosphamide/dexamethasone (Cy-Dex) regimen is a combination chemotherapy pairing the alkylating agent cyclophosphamide with the corticosteroid dexamethasone, used to treat multiple myeloma and, in cyclophosphamide–steroid combinations, other hematologic malignancies such as stage III–IV lymphoma.[1](https://pubmed.ncbi.nlm.nih.gov/17973267/) • [2](https://www.ncbi.nlm.nih.gov/books/NBK553087/) It served as an induction regimen before autologous stem cell transplantation (ASCT) in newly diagnosed myeloma and as a backbone for later triplets, but current guidelines no longer feature the standalone doublet, favoring bortezomib- and lenalidomide-based combinations and daratumumab- or isatuximab-based quadruplets.[3](https://www.uptodate.com/contents/treatment-protocols-for-multiple-myeloma) • [4](http://www.ingentaconnect.com/content/wk/jco/2026/00000044/00000010/art00011)\n\n| Fact | Detail |\n|---|---|\n| Components | Cyclophosphamide (nitrogen mustard alkylating agent) plus dexamethasone (glucocorticoid)[2](https://www.ncbi.nlm.nih.gov/books/NBK553087/) |\n| NMSG induction dosing | Cyclophosphamide 1,000 mg/m² day 1; dexamethasone 40 mg/day days 1–4 and 9–12; repeated day 22[1](https://pubmed.ncbi.nlm.nih.gov/17973267/) |\n| Key trial result | Median event-free survival 29 months and 3-year overall survival 75%, equivalent to VAD[1](https://pubmed.ncbi.nlm.nih.gov/17973267/) |\n| Triplet successor | CyBorD gave ≥ partial response in 88% of newly diagnosed patients[5](https://pmc.ncbi.nlm.nih.gov/articles/PMC2711213/) |\n| Main toxicities | Myelosuppression with sepsis risk, infection, hemorrhagic cystitis, steroid effects, secondary malignancies[2](https://www.ncbi.nlm.nih.gov/books/NBK553087/) |\n| Current status | Superseded as first-line therapy by daratumumab/isatuximab quadruplets per 2026 ASCO–Ontario Health guideline[4](http://www.ingentaconnect.com/content/wk/jco/2026/00000044/00000010/art00011) |\n\n## How it works\n\nCyclophosphamide is a nitrogen mustard alkylating agent that is not cell-cycle phase specific. Hepatic CYP enzymes convert it to aldophosphamide, which is cleaved into phosphoramide mustard and acrolein. Phosphoramide mustard forms cross-linkages within and between adjacent DNA strands at the guanine N-7 position; these modifications are permanent and eventually lead to programmed cell death. Acrolein has no antitumor activity but causes hemorrhagic cystitis.[2](https://www.ncbi.nlm.nih.gov/books/NBK553087/)\n\nDexamethasone contributes independently: in resistant myeloma, high-dose dexamethasone alone induced remissions in 4 of 19 patients (21%), compared with 11 of 17 (65%) for VAD, establishing single-agent corticosteroid activity in myeloma while leaving the added value of the vinca alkaloid and anthracycline components unclear.[6](https://www.acpjournals.org/doi/10.7326/0003-4819-105-1-8) Pairing an alkylator with a steroid therefore combines two agents with distinct mechanisms, and the pair replaced the vincristine and doxorubicin infusion components of VAD in several settings.[6](https://www.acpjournals.org/doi/10.7326/0003-4819-105-1-8)\n\n## How it is done\n\nIn the Nordic Myeloma Study Group (NMSG) randomized trial, Cy-Dex was given as cyclophosphamide 1,000 mg/m² intravenously on day 1 with dexamethasone 40 mg/day on days 1–4 and 9–12, repeated on day 22, for two courses before high-dose melphalan and ASCT.[1](https://pubmed.ncbi.nlm.nih.gov/17973267/) Oral weekly variants are also documented: the Oxford CTD protocol doses cyclophosphamide 500 mg once weekly (or 50–100 mg daily) with dexamethasone 40 mg daily on days 1–4 and 12–15 of 21-day cycles.[7](https://nssg.oxford-haematology.org.uk/myeloma/pdf-protocols/MM-10-ctd-full-dose.pdf)\n\nSupportive care is part of the regimen. Management of cyclophosphamide includes complete blood count monitoring, hydration, mesna prophylaxis against hemorrhagic cystitis, and G-CSF; the drug should not be given with neutrophils ≤1,500/mm³ or platelets <50,000/mm³.[2](https://www.ncbi.nlm.nih.gov/books/NBK553087/) A 2024 CyBorD cohort additionally gave all patients acyclovir and sulfamethoxazole-trimethoprim prophylaxis.[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC11016155/) In elderly patients, the dexamethasone dose should be reduced, for example to 20 mg once weekly.[9](https://www.cancercareontario.ca/en/drugformulary/regimens/monograph/47781) A 2025 review reports that robust data support planned dexamethasone discontinuation after one to two cycles in older and frailer patients with newly diagnosed myeloma.[10](https://www.ingentaconnect.com/content/10.1200/JCO-25-01713)\n\n## Origin\n\nPublished sources do not identify an original describer of the cyclophosphamide/dexamethasone doublet, so its authorship cannot be attributed here. Its lineage is traceable through VAD (vincristine, doxorubicin, dexamethasone), which as first-line therapy in 32 previously untreated myeloma patients produced an 84% overall response rate with 28% complete remission and a projected median survival of 44 months, and through VAD-based primary regimens that substituted cyclophosphamide for the vinca/anthracycline pair in 175 previously untreated patients, achieving a 55% response rate.[6](https://www.acpjournals.org/doi/10.7326/0003-4819-105-1-8) • [11](https://staging.europepmc.org/article/MED/2571813) • [12](https://onlinelibrary.wiley.com/doi/10.1002/ajh.2830330203) The doublet entered routine induction practice through the NMSG randomized trial, which accrued 315 patients under age 65 between November 2001 and October 2003 and compared Cy-Dex with VAD before ASCT.[1](https://pubmed.ncbi.nlm.nih.gov/17973267/)\n\n## Variants\n\n**CVAD and CTD.** In MRC Myeloma IX, CVAD combined oral cyclophosphamide 500 mg/week, vincristine 0.4 mg/day, doxorubicin 9 mg/m²/day by continuous infusion for 4 days, and dexamethasone 40 mg/day on days 1–4 and 12–15; CTD replaced the vincristine and doxorubicin with thalidomide 100–200 mg/day.[13](https://haematologica.org/article/view/6249/)\n\n**CyBorD and CVD.** Adding bortezomib (1.3 mg/m² on days 1, 4, 8, 11) to weekly oral cyclophosphamide 300 mg/m² and dexamethasone 40 mg produced an 88% intent-to-treat ≥ partial response rate, 61% ≥ very good partial response, and 39% CR/nCR in a phase II trial of 33 newly diagnosed patients.[5](https://pmc.ncbi.nlm.nih.gov/articles/PMC2711213/) In Myeloma XI, response-adapted CVD intensification improved median progression-free survival to 30 versus 20 months (HR 0.60, \\( p < 0.0001 \\)) without changing 3-year overall survival.[14](https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026%2819%2930167-X/fulltext)\n\n**Mitoxantrone mobilization.** A registered protocol (NCT00005987) uses a priming phase of cyclophosphamide IV over 2 hours on day 1, mitoxantrone IV daily on days 1–2, and dexamethasone IV every 12 hours for 4 doses, with GM-CSF versus G-CSF for stem cell mobilization and peripheral blood stem cells collected on days 11–13.[15](https://ichgcp.net/clinical-trials-registry/NCT00005987) [Cyclophosphamide](https://www.edgepedia.org/cyclophosphamide) 2 g/m² plus filgrastim 5 µg/kg also remains in use for mobilization after lenalidomide-based induction.[16](https://www.nature.com/articles/bmt2015236)\n\n## Applications\n\nCy-Dex was established as induction before ASCT in transplant-eligible newly diagnosed myeloma: in the NMSG trial, ASCT rates were similar (VAD 86% vs Cy-Dex 87%), 4-month early mortality favored Cy-Dex (1.9% vs 5.8%, P=.08), and both arms reached a median event-free survival of 29 months with 3-year overall survival of 75%.[1](https://pubmed.ncbi.nlm.nih.gov/17973267/) A short course of cyclophosphamide does not affect stem cell harvest or transplantation.[1](https://pubmed.ncbi.nlm.nih.gov/17973267/) In relapsed/refractory myeloma, the GEM-KyCyDex randomized phase II study found that adding cyclophosphamide to carfilzomib–dexamethasone did not improve overall progression-free survival (19.1 vs 16.6 months, \\( P = 0.577 \\)), though the lenalidomide-refractory subgroup benefited (18.4 vs 11.3 months, HR 1.7, \\( P = 0.043 \\)), at the cost of more severe infections (7% vs 2%).[17](https://haematologica.org/article/view/11068) Cyclophosphamide itself carries FDA indication for stage III–IV malignant lymphomas and has been used with corticosteroids in multiple myeloma, CLL, and other malignancies.[2](https://www.ncbi.nlm.nih.gov/books/NBK553087/)\n\n## Limitations and alternatives\n\nCyclophosphamide toxicities include myelosuppression with sepsis risk, cardiotoxicity, pulmonary toxicity, veno-occlusive liver disease, hemorrhagic cystitis, and secondary malignancies, with higher dosages associated with greater incidence and mortality.[2](https://www.ncbi.nlm.nih.gov/books/NBK553087/) In MRC Myeloma IX, severe cytopenias and infection were more frequent with CVAD than CTD, while grade 3 constipation and somnolence were more common with CTD; CTD was non-inferior for progression-free and overall survival (per-protocol median PFS 27 vs 25 months, HR 0.94, \\( P = 0.56 \\)).[13](https://haematologica.org/article/view/6249/) [Dexamethasone](https://www.edgepedia.org/dexamethasone) adds dose-dependent toxicities including cataracts and infections, and its contribution to triplet and quadruplet regimens is uncertain even though it adds value within doublets in relapsed/refractory disease.[10](https://www.ingentaconnect.com/content/10.1200/JCO-25-01713)\n\nAgainst alternatives, a three-way comparison of lenalidomide–dexamethasone, CRd, and CyBorD in newly diagnosed myeloma found no significant differences in progression-free survival (median 2.3 vs 2.7 years, \\( P = 0.11 \\)) or 3-year overall survival (88% vs 79% vs 88%, \\( P = 0.23 \\)).[18](https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2011.08949.x) Adding cyclophosphamide to bortezomib–dexamethasone improved stem cell collection (9.9 vs \\( 7.7 \\times 10^{6} \\) cells/kg, \\( p = 0.007 \\)) but not day +100 responses or progression-free survival.[19](https://www.mdpi.com/1718-7729/27/2/5385) VCD achieved at least very good partial response in 54% of patients after four induction cycles versus 42.8% for CTD.[20](https://pubmed.ncbi.nlm.nih.gov/31537476/) After CyBorD induction and melphalan autograft, one cohort associated G-CSF-only mobilization with better overall survival than cyclophosphamide-containing mobilization (aHR 0.60, \\( p = 0.018 \\)).[21](https://www.nature.com/articles/s41409-021-01300-2)\n\nThe doublet has been superseded. Current UpToDate protocol listings feature VCD/CyBorD and VRd for initial treatment, with no standalone cyclophosphamide/dexamethasone doublet among featured regimens.[3](https://www.uptodate.com/contents/treatment-protocols-for-multiple-myeloma) The 2026 ASCO–[Ontario Health](https://www.edgepedia.org/ontario-health) guideline recommends quadruplet therapy with daratumumab or isatuximab combined with bortezomib, lenalidomide, and dexamethasone, and at least lenalidomide maintenance.[4](http://www.ingentaconnect.com/content/wk/jco/2026/00000044/00000010/art00011) IFM 2026 recommendations likewise keep daratumumab–lenalidomide–dexamethasone as the backbone for transplant-ineligible patients, adding bortezomib in fit patients.[22](https://doi.org/10.1016/j.clml.2026.09.002)\n\n## References\n\n1. [Cyclophosphamide plus dexamethasone is an efficient initial treatment before high-dose melphalan and autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: results of a randomized comparison with VAD (Nordic Myeloma Study Group)](https://pubmed.ncbi.nlm.nih.gov/17973267/)\n2. [Cyclophosphamide - StatPearls - NCBI Bookshelf](https://www.ncbi.nlm.nih.gov/books/NBK553087/)\n3. [Treatment protocols for multiple myeloma - UpToDate](https://www.uptodate.com/contents/treatment-protocols-for-multiple-myeloma)\n4. [Treatment of Multiple Myeloma: ASCO–Ontario Health (Cancer Care Ontario) guideline](http://www.ingentaconnect.com/content/wk/jco/2026/00000044/00000010/art00011)\n5. [Cyclophosphamide, bortezomib and dexamethasone (CyBorD) induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial](https://pmc.ncbi.nlm.nih.gov/articles/PMC2711213/)\n6. [High-Dose Glucocorticoid Treatment of Resistant Myeloma](https://www.acpjournals.org/doi/10.7326/0003-4819-105-1-8)\n7. [Oxford Myeloma Group CTD full-dose protocol](https://nssg.oxford-haematology.org.uk/myeloma/pdf-protocols/MM-10-ctd-full-dose.pdf)\n8. [Improved long-term survival rate in the responders to bortezomib, cyclophosphamide, dexamethasone induction therapy in a transplant-eligible cohort of predominantly middle-age multiple myeloma patients](https://pmc.ncbi.nlm.nih.gov/articles/PMC11016155/)\n9. [Cancer Care Ontario drug formulary regimen monograph (cyclophosphamide/dexamethasone/lenalidomide)](https://www.cancercareontario.ca/en/drugformulary/regimens/monograph/47781)\n10. [Past, Present, and Future of Dexamethasone in Multiple Myeloma](https://www.ingentaconnect.com/content/10.1200/JCO-25-01713)\n11. [Infusion of vincristine and doxorubicin with oral dexamethasone as first-line therapy for multiple myeloma.](https://staging.europepmc.org/article/MED/2571813)\n12. [VAD-based regimens as primary treatment for multiple myeloma](https://onlinelibrary.wiley.com/doi/10.1002/ajh.2830330203)\n13. [Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC Myeloma IX randomized trial results](https://haematologica.org/article/view/6249/)\n14. [Response-adapted intensification with cyclophosphamide, bortezomib, and dexamethasone versus no intensification in patients with newly diagnosed multiple myeloma (Myeloma XI)](https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026%2819%2930167-X/fulltext)\n15. [Cyclophosphamide and mitoxantrone hydrochloride and dexamethasone in Multiple Myeloma and Plasma Cell Neoplasm - ICH GCP registry (NCT00005987)](https://ichgcp.net/clinical-trials-registry/NCT00005987)\n16. [A randomized phase II study of stem cell mobilization with cyclophosphamide+G-CSF or G-CSF alone after lenalidomide-based induction in multiple myeloma](https://www.nature.com/articles/bmt2015236)\n17. [Randomized phase II study of weekly carfilzomib 70 mg/m² and dexamethasone with or without cyclophosphamide (GEM-KyCyDex)](https://haematologica.org/article/view/11068)\n18. [A comparison of lenalidomide/dexamethasone versus cyclophosphamide/lenalidomide/dexamethasone versus cyclophosphamide/bortezomib/dexamethasone in newly diagnosed multiple myeloma](https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2011.08949.x)\n19. [Cyclophosphamide–Bortezomib–Dexamethasone Compared with Bortezomib–Dexamethasone in Transplantation-Eligible Patients with Newly Diagnosed Multiple Myeloma](https://www.mdpi.com/1718-7729/27/2/5385)\n20. [Superiority of the triple combination of bortezomib, cyclophosphamide and dexamethasone versus cyclophosphamide, thalidomide and dexamethasone in patients with newly diagnosed multiple myeloma, eligible for transplantation](https://pubmed.ncbi.nlm.nih.gov/31537476/)\n21. [The association of mobilising regimen on immune reconstitution and survival in myeloma patients treated with bortezomib, cyclophosphamide and dexamethasone induction followed by a melphalan autograft](https://www.nature.com/articles/s41409-021-01300-2)\n22. [IFM 2026 Recommendations for First-Line Treatment of Newly Diagnosed Multiple Myeloma](https://doi.org/10.1016/j.clml.2026.09.002)\n\n---\n*Topic: Encyclopedia › Life and health › Human health and medicine › Medicines and therapeutics › Cancer chemotherapy and regimens › Multiple myeloma and hematologic regimens*\n\n*Initially written Sep 29, 2026 · Edited: Oct 15, 2026*\n\n*Copyright 2026 EdgeChat AI, a subsidiary of Biostate AI.*\n\nLicense: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license\n", "same_as": [], "url": "https://www.edgepedia.org/cyclophosphamide-dexamethasone-regimen", "markdown_url": "https://www.edgepedia.org/cyclophosphamide-dexamethasone-regimen.md", "license": { "name": "Edgepedia Community License 1.0", "url": "https://www.edgepedia.org/edgepedia/license", "summary": "Free with credit, commercial use included. AI training is open to everyone. For other uses, organizations over USD 100M in revenue or 100M monthly users license separately.", "spdx": "LicenseRef-Edgepedia-Community-1.0" }, "credit": "\"Cyclophosphamide/dexamethasone regimen\", Edgepedia (EdgeChat), https://www.edgepedia.org/cyclophosphamide-dexamethasone-regimen. Edgepedia Community License 1.0.", "credit_md": "\"[Cyclophosphamide/dexamethasone regimen](https://www.edgepedia.org/cyclophosphamide-dexamethasone-regimen)\", Edgepedia (EdgeChat), [https://www.edgepedia.org/cyclophosphamide-dexamethasone-regimen](https://www.edgepedia.org/cyclophosphamide-dexamethasone-regimen). [Edgepedia Community License 1.0](https://www.edgepedia.org/edgepedia/license).", "credit_html": "\"Cyclophosphamide/dexamethasone regimen\", Edgepedia (EdgeChat), https://www.edgepedia.org/cyclophosphamide-dexamethasone-regimen. Edgepedia Community License 1.0.", "speakable": "The cyclophosphamide/dexamethasone regimen is a chemotherapy combination pairing the alkylating agent cyclophosphamide with the corticosteroid dexamethasone, formerly used as induction therapy for multiple myeloma before stem cell transplantation." }